Chronic Lung Disease of Infancy
Early contributions were focused upon the regulation of perinatal pulmonary vascular tone. Our Laboratory addressed the subcellular mechanisms that underlie the postnatal adaption of the pulmonary circulation. Key publications demonstrated that pulmonary artery endothelial cells produced endothelial-derived relaxing factor (EDRF), subsequently identified as nitric oxide (NO), in response to ventilation, oxygenation and shear stress. Further work demonstrated that oxygen, one of the key stimuli for perinatal pulmonary vasodilation, as well as NO acts via quantal and localized release of calcium from ryanodine-sensitive stores to prompt activation of the pulmonary artery smooth muscle cell calcium-sensitive potassium channels. These papers informed the development of several clinical trials wherein the efficacy of inhaled nitric oxide in persistent pulmonary hypertension of the newborn was established.
With improved obstetrical and neonatal care, more, smaller and less developmentally mature infants are surviving even extreme prematurity. Our Laboratory is interested in two fundamental questions surrounding chronic lung disease of infancy. First, whether and how might exposure of oxygen levels in excess of the normally low intrauterine oxygen tension state of the intrauterine environment might compromise lung development. Second, as pulmonary hypertension complicates chronic lung disease of infancy in ~30% of cases, our Laboratory is focusing on the molecular mechanisms that underlie the increase in pulmonary artery blood pressure and identification of novel therapeutic tools to control blood pressure and promote lung development.
Projects
Embryonic Lethality in Mice Lacking SM22a-PHD1/2/3
Researchers: Elizabeth A. Barnes, Reiji Ito, and David N. Cornfield
PHD proteins have redundant and non-redundant functions. The loss of all three isoforms of PHD in SM22a-expressing cells is embryonic lethal, indicating that PHD expression in SM22a-expressing cells is essential for life.
Lung development with loss of HIF-1α promotes BPD phenotype
Researchers: Reiji Ito, Xibing Che, Elizabeth A. Barnes, David N. Cornfield
In lung development, the most important process in alveolarization is when alveolar ducts divide into alveolar sacs by secondary septation due to angiogenesis driven by Vascular-endothelial growth factor (VEGF). It is known that the treatment with oxygen supplementation and manualized ventilation for preterm infants, especially less than 28 weeks gestational age, causes arrested lung development with impaired alveolariation and interrupted angiogenesis, and results in Bronchopulmonary Dysplasia (BPD).
HIF-1α is one of the important transcription factors for angiogenesis and plays a central role in angiogenesis via transcription of VEGF and so on. Although the experimental inhibition of HIF-1α caused a BPD phenotype in animal lung, the molecular mechanisms remain unknown.
To clarify the effects of HIF-1α, we created mice with a cell-specific deletion of HIF-1α, and their lungs show impaired development consistent with BPD with
Metabolism of Pulmonary Artery Smooth Muscle Cells from Patients with Pulmonary Hypertension
Researchers: Elizabeth A. Barnes, Riddhita Mukherjee, Bereketeab Haileselassie, and David N. Cornfield
Controversy exists regarding the metabolic state of smooth muscle cells (SMC) from pulmonary hypertensive (PH) patients. Therefore, we have examined SMC from PH patients in comparison to SMC. Preliminary results show that SMC from PH patients differ greatly compared to controls in that they are more adaptable to various cellular environments.
Oxygen consumption rates (OCR) of control (C1, C3, C4) and PH (IPAH1, IPAH 5, IPAH6) SMC. PH SMC exhibit enhanced ATP synthesis under conditions of cellular stress. PH SMC metabolic adaptability may play a role in the pathogenesis of PH.
The role of HIF-1α in a Murine Model of BPD
Researchers: Reiji Ito, Xibing Che, Elizabeth A. Barnes, David N. Cornfield
The cell-specific deletion of HIF-1α caused the phenotype of BPD, but this mechanism remains unknown. To clarify the role of HIF-1α in lung development, we created mice with a cell-specific stabilization of HIF-1α. These mice appear to be protected when exposed to hyperoxic-induced lung injury.
The lungs from these mice had more alveolarization and vascularization, and less hypertrophy of septal thickness and apoptosis than wild-type, significantly.
Chronic Lung Injury caused by BPD
Researchers: Reiji Ito, Xibing Che, Elizabeth A. Barnes, David N. Cornfield
In BPD, lung function continues to deteriorate until adulthood leading to obstructive lung disease. Moreover, about 20% of BPD patients suffer from pulmonary hypertension (PH), and especially show higher mortality with up to 50% per 2 years after diagnosed with PH.
In our animal model with a cell-specific stabilization of HIF-1α, pulmonary arterial medial wall thickness and right ventricular hypertrophy was significantly suppressed compared to wild-type at 14 days of age.
In BPD, the pulmonary artery pressure is supposed to be elevated with age by hypoplastic vasculature. But this mechanism remains unknown.
To clarify this mechanism, our animal models will be studied after they reach maturity.
The SM22a-HIF-1a Mouse as a Model for Bronchopulmonary Dysplasia
Researchers: Elizabeth A. Barnes, Chihhsin Chen, Xibing Che, Ross Metzger, Cristina Alvira, and David N. Cornfield
Bronchopulmonary dysplasia (BPD) affects infants born prematurely due to the lack of mature lung function. HIF-1a has been found to be an invaluable component in the maturing lung; therefore, we made a mouse lacking SMC-HIF-1a and found that these mice maintain an immature lung phenotype, resembling the human condition.
Mice without SMC-HIF-1a display disorganized elastin (brown) expression (right panels), consistent with BPD. Magnification 200x, calibration bar 200mm. 3d, 3 day old mice; 8d, 8 day old mice; Adult, adult mice.
People
Cristina Alvira, M.D.
Elizabeth A. Barnes, Ph.D.
Xibing Che, Ph.D.
Chihhsin Chen. M.S.
David N. Cornfield, M.D.
Bereketeab Haileselassie, M.D.
Reiji Ito, M.D., Ph.D.
Ross J. Metzger, Ph.D.
